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A centre focusing on hepatocellular carcinoma research

Under its director, Prof. Dr. Peter Schirmacher, the Institute of Pathology at the University of Heidelberg has become a major liver cancer research centre, with a particular focus on hepatocellular carcinoma. The institute is looking for new diagnostic markers and new molecular targets for drugs that have the potential to be used for specifically treating this cancer.

The Institute of Pathology at the University of Heidelberg receives around 62,000 samples per year from all areas of medicine on which it carries out tissue (histology) and cell (cytology) investigations aimed at finding cellular changes in order to diagnose diseases. The samples come from Heidelberg University Hospital as well as twenty other hospitals and several specialist practices. This makes the institute the largest of its kind in Germany. Besides its broad range of activities in patient treatment, research, teaching, further training and quality management and autopsy, the institute is also a Germany-wide reference centre for numerous special areas, in which it provides consulting services to colleagues who seek cooperative support in the diagnosis or confirmation of diseases.

Pathology reference services offered by the Institute of Pathology

The decision on which kind of therapy is best to effectively treat a certain disease often depends on the correct evaluation of a tissue sample. For example, providing information about the type of tumour ("typing"), its aggressiveness ("grading") and extent and spread ("staging") makes a pathologist a "therapy pilot". In some problematic cases (often less than two per cent of all diagnoses), the pathologists will either ask for the diagnostic expertise of a specialist or will choose to use special technical equipment at other hospitals or institutes. Pathology reference services are important tools to ensure the quality of diagnosis and hence the responsible treatment of patients. In order to be able to deal effectively with frequent consultancy requests and facilitate communication, the Department of General Pathology (Director: Prof. Dr. Peter Schirmacher) at the University of Heidelberg has combined its services in a "Reference Centre" as well as standardising its procedures.

The centre's specialist reference areas are: hepatology, gastroinstestinal pathology, pancreatic pathology, haematopathology, breast pathology, cardiopulmonary pathology and the pathology of supporting tissue and soft tissue tumours. The National Centre for Tumour Diseases (NCT) also contacts the Reference Centre for a confirmation of diagnosis (pathology review), especially in the case of complex tumour diseases. The Reference Centre therefore works closely with and supports the NCT in its efforts to offer innovative and high-level tumour treatment.

Leading centre in liver cancer research

Professor Dr. Peter Schirmacher, Director of the Institute of Pathology at the University Hospital in Heidelberg and spokesperson of the new collaborative research center. © University Hospital Heidelberg

In addition to diagnostic patient treatment and pathology reference services, the Institute of Pathology carries out scientific research on liver and gastrointestinal diseases (hepatogastroenterological pathology). Under its director, Prof. Dr. Peter Schirmacher, the institute has become an international leader in the investigation of the molecular mechanisms and treatment of liver cell cancer (hepatocellular carcinoma, HCC). Schirmacher, who became head of the Department of Pathological Anatomy in Heidelberg in 2004, had already previously focused on chronic liver diseases and the molecular mechanisms that lead to hepatocellular carcinoma during his stays at the pathology institutes at the Universities of Mainz and Cologne and at the Albert Einstein College in New York. Schirmacher received the Boehringer Ingelheim Prize in 1997 for this work.

A new Transregio collaborative research centre (SFB/TRR 77) was set up in January 2010. The SFB/TTR 77 "Liver cancer - from the molecular mechanisms of cancer development to specific therapies" has been given funding of 12 million euros for four years by the DFG (German Research Foundation). Prof. Schirmacher is the spokesperson of the SFB/TRR 77, which brings together 40 scientists from the University of Heidelberg, the German Cancer Research Center, the Hanover Medical School and the Helmholtz Centre for Infection Research (Braunschweig). Germany's leading liver cancer experts are looking for answers to the question as to how chronic liver diseases turn into metastatic tumours and the experts are thus contributing to the development of new strategies for the prevention, diagnosis and treatment of this cancer. Currently, the treatment of hepatocellular carcinoma still has a poor outcome.

Search for new diagnostic markers

Incidence of liver cancer worldwide © WHO
The most common malignant tumours found in the liver are cancerous tumours (metastases) that have spread to the liver from elsewhere in the body and liver cancer that starts in the liver (hepatocellular carcinoma, HCC). HCC causes around one million deaths per year, making it the fifth most frequent tumour worldwide. HCC is very common in tropical Africa and Southeast Asia, including Southern China. However, the incidence of HCC has also considerably increased over the last few years in Germany and other Western industrialised countries. It is assumed that the number of HCC cases will continue to increase in the future. Around 90 per cent of all HCC cases are secondary to either hepatitis B or C infection (chronic inflammation), alcoholism and a number of other diseases (e.g., non-alcohol related cirrhosis of the liver). HCC has a very poor outcome since the tumour has already grown to a considerable size and since non-cancerous tissue is extremely cirrhotic at the time of diagnosis. Surgical resection to completely remove the tumour and, if necessary, liver transplantation offers the best prognosis for long-term survival, but unfortunately only around 5% of patients are suited to surgical resection or transplantation. Radiation therapy, chemotherapy or immunotherapy do not offer effective treatment. Early-stage hepatocellular carcinomas are difficult to diagnose with imaging methods, and no sensitive diagnostic markers are currently available. Dr. Thomas Longerich’s team from the Institute of Pathology is focused on the identification of molecular markers to gain information on the stage and progression of HCC. In cooperation with the Department of Molecular Genetics at the German Cancer Research Center led by Prof. Dr. Peter Lichter, Dr. Thomas Longerich’s team is carrying out high-resolution genomic and epigenomic profiling analyses using microarrays. Using a clinically well-defined HCC patient collective, the researchers’ goal is to find ways to enable the molecular classification of the cancer and its precursor lesions. In addition, they hope to find suitable target genes for the prognosis and diagnosis of hepatocellular carcinoma.

New molecular targets for the treatment of hepatocellular carcinoma

Localisation of Polo-like kinases in the mitotic spindle. © EMBO

As reported by Prof. Schirmacher (quoted in Ruperto Carola (research magazine of the University of Heidelberg) 2/2007), the Institute of Pathology carries out investigations using multitissue arrays, a high-throughput technology that allows the investigation of identified genetic alterations of a large number of tumours. This enables the researchers to quickly identify potential marker genes and test them for their suitability as therapeutic targets. The researchers were able to show that the dysregulation of growth factor signalling pathways play an important role in the development and growth of liver cancer cells. The regulation of growth factor signalling pathways involves protein kinases, which however have a broad range of effects. In a recently published study (Pellegrino et. al., Hepatology 51, 857-868, 2010), Schirmacher and his team were able to show that Polo-like kinases (PLK proteins), which are important cell-cycle regulators, have different roles in human HCC: PLK1 is an oncogene while PLK2-4 are most likely tumour suppressor genes.

The molecular changes are highly complex since the different growth factor signalling pathways are not independent from each other, but interact closely with each other. The growth factor signalling pathways are suitable targets for the treatment of hepatocellular carcinoma; however, the challenge is to identify and target the key components of these pathways. 

Human liver with hepatocellular carcinoma. © Charité, Berlin

The researchers from Heidelberg have identified other target structures that have the potential to be used as therapeutic targets. The researchers' main focus centres on the prostaglandin metabolism, in which they hope to inhibit cyclooxygenase-2 (COX-2), an enzyme that catalyses the conversion of arachidonic acid into prostaglandins. In contrast to COX-1, which is related to COX-2, the latter is only produced in minute quantities in healthy tissue. Larger COX-2 quantities are found in inflammatory diseases and tumours. Therefore, strategies that focus on the treatment of tumours by inhibiting COX-2 expression need to target and destroy diseased tissue, but damage healthy tissue as little as possible.

Nonsteroidal anti-inflammatory drugs (NSAIDs or NAIDs), which are drugs with anti-inflammatory and analgesic effects, exert their effect by inhibiting COX-2. Recent research has shown that the NSAID-mediated inhibition of the prostaglandin metabolism has an anti-tumour and tumour-preventive effect: patients who are taking nonsteroidal anti-inflammatory drugs over a longer period of time, run a lesser risk of developing malignant tumours. In addition, COX-2 inhibitors have been shown to retard cancer growth in a rare genetic disease that leads to colon cancer (polyposis of the colon).

It has long been assumed that COX-2 inhibitors exert their anti-tumour effect by suppressing tumour angiogenesis, i.e. preventing the growth of new vessels required by the tumour for the supply of nutrients and oxygen. However, the investigations carried out by Schirmacher and his team have shown that COX-2 inhibitors have a direct effect on the growth of tumour cells. In addition, COX-2 inhibitors induce the tumour to undergo apoptosis (programmed cell death) either through the extrinsic signalling pathway (involving death receptors on the cell surface) or through the intrinsic signalling pathway (initiated by proteins released from the mitochondria). The anti-tumour effect of COX-2 inhibitors was shown in tumour cell cultures and in animal experiments. Human clinical trials have also shown that COX-2 inhibitors drugs have an anti-tumour effect. New approaches are focusing to an increasing extent to effectively combine the aforementioned options for the treatment of hepatocellular carcinoma.

Further information:
Prof. Dr. med. Peter Schirmacher
Managing Director
Institute of Pathology
University of Heidelberg
Im Neuenheimer Feld 220/221
69120 Heidelberg
Email: Peter.schirmacher(at)med.uni-heidelberg.de
Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/a-centre-focusing-on-hepatocellular-carcinoma-research